Dehydroepiandrosterone

Scientific Name(s):Dehydroepiandrosterone and dehydroepiandrosterone sulfate

Common Name(s): DHEA , DHEAS , prasterone

Uses

Adequately powered, long-term clinical trials are lacking to support a place in therapy for dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) supplementation (henceforth, jointly referred to as DHEA/S). Reviews of clinical trials found no convincing evidence to support a place in therapy for postmenopausal symptoms in women, in improving cognitive function or physical strength in elderly patients, in hyperlipidemia or insulin resistance, or in schizophrenia or cancer. Some evidence exists to support the use of DHEA/S supplementation in women with diminished ovarian reserves, in subpopulations of elderly women with osteoporosis, and in mild systemic lupus erythematosus.

Dosing

Orally administered DHEA has a less than 10% bioavailability and is converted into inactive DHEAS, which can then act as a reservoir for the body to utilize. Daily dosing of DHEA 25 mg has been suggested in postmenopausal women because this dose minimizes the adverse androgenic effects; however, only studies in which at least 50 mg/day were used demonstrated positive outcomes. Dosages used in clinical studies of assisted reproduction were in the range of 50 to 75 mg/day (in divided doses). In adrenal insufficiency, DHEA 50 mg/day for 3 months is considered a replacement dose, while 200 mg/day achieves supraphysiological circulating levels and would thus be considered a pharmacological dose.

Contraindications

Contraindications have not been identified. Use of DHEA or DHEAS is not recommended in breast or prostate cancer.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. DHEA supplementation has been evaluated to improve oocyte production in infertility.

Interactions

None well documented.

Adverse Reactions

Studies in adrenal insufficiency suggest DHEA is generally well tolerated. However, data from long-term studies are lacking. Observed adverse effects include acne, hirsutism, and decreased high-density lipoprotein (HDL) levels.

Toxicology

Information in humans is limited. DHEA has been shown to be carcinogenic as well as protective against certain cancers in rodents.

Many nonprescription preparations of DHEA originate from China and are likely to contain DHEA derived from diosgenin extracted from the root of wild yam ( Dioscorea villosa ). Other commercial preparations contain synthetically derived DHEA. These supplements are not regulated by the US Food and Drug Administration and are exempt from pharmaceutical quality standards; wide variations in the content of DHEA have been described. 1 , 2

History

DHEA was first isolated by the German biochemist Adolf Butenandt in the 1930s. Claims for DHEA supplementation as the “fountain of youth” hormone have arisen largely from the observation that endogenous levels of the hormone decline with age and from anecdotal descriptions of enhanced energy and well-being in patients treated with DHEA for adrenal insufficiency. Although its use is prohibited under the World Anti-Doping Code and the National Collegiate Athletic Association, several high-profile athletes have tested positive for DHEA. 2 , 3 The FDA banned over-the-counter sales of DHEA in 1985; however, since the passage of the dietary supplement Health and Education ACT of 1994, DHEA has been marketed as a dietary supplement. 2

Chemistry

DHEA is a weak androgen and acts as a precursor in the production of sex hormones. 1 It is produced endogenously in the adrenal gland from cholesterol, but can also be synthesized in neurons and glial cells. 3 , 4 Both DHEA and its main metabolite dehydroepiandrosterone sulfate (DHEAS) are major circulating hormones in the body. Levels vary according to age, peaking in early adulthood and declining to 10% to 20% between 70 and 80 years of age. 3 , 5 Other factors that influence circulating DHEA/S levels include alcohol intake, body mass index, ethnicity, nutritional status, gender, smoking, thyroid function, and concomitant medications such as corticosteroids. 1

Uses and Pharmacology

Animal data

Studies conducted in nonprimate animals have limited applicability in humans because the levels of circulating DHEA/S are different; rodents have very little circulating DHEA. 3 , 5 , 6

Assisted reproduction

Limited clinical studies have been conducted in women with diminished ovarian reserves. Reviews of the studies have concluded that DHEA supplementation increases the number of oocytes produced, and hence increases the chance of pregnancy. The rate of miscarriage was also found to be diminished, possibly by reducing aneuploidy. Reported adverse events are androgenic in nature, but also include 1 case report of seizure and the potential for male sex bias due to increased intrafollicular testosterone. 7 , 8 , 9

Cancer

The relevance of rodent models of cancer is unclear. 10 , 11 Epidemiological data are inconclusive regarding the role of DHEA and DHEAS in cancer. Some studies suggest that the age-related decline in DHEA/S, testosterone, and estrogen is protective for hormone-sensitive cancers. Other studies correlate elevated DHEA/S with decreased rates of cancer. 10 , 11 , 12

DHEA is a weak androgen, and adrenal androgens are associated with an increased risk of cancer, especially of the breast and prostate. Until rigorous laboratory and clinical studies have been conducted, the use of DHEA/S in cancer prevention is not supported. 11 , 12

Cognition

Circulating DHEA levels in elderly patients are only 10% to 20% of those in young adults, and some but not all observational studies suggest patients diagnosed with dementia have lower circulating DHEA/S levels. 1 , 3 , 4 , 5 This observation has led to the concept that DHEA supplementation might prevent or slow the decline in cognitive function with age; however, there is currently no positive evidence to support this notion. 3 , 4 , 6 , 13

Metabolic effects (lipids/insulin)

Studies evaluating the effect of DHEA supplementation on lipid profiles have produced equivocal results. Dosages used in the trials vary from 25 to 1,600 mg/day and include heterogenous populations, making meta-analysis difficult. Some studies report decreases in total cholesterol as well as decreased HDL cholesterol; other studies report no effect. It is possible that subpopulations may benefit; however, these are yet to be identified. 1 , 14 , 15 , 16 Similarly, results for body composition and body fat distribution outcomes are inconsistent. 1 , 16 The role of exogenous DHEA in insulin sensitivity is unclear. Some studies report a modest effect, while a greater number show no effect. 16 , 17

Postmenopausal effects

Reviews of clinical trials and 1 meta-analysis of DHEA supplementation found no convincing evidence to support a place in therapy for postmenopausal symptoms in women with intact adrenal function. 1 , 4 , 6 , 15 , 18 , 19 Sexual function, well-being, quality of life measures, metabolic parameters (lipid profile, carbohydrate metabolism), and cognition were among the outcomes measured. DHEAS has been shown to stimulate osteoblasts; however, results for improvements in bone density are equivocal, with only a small effect demonstrated in some studies. A benefit from DHEAS supplementation may be seen in elderly women with low circulating DHEA, but not in elderly men. Fracture rates were not reported in the studies. 1 , 4 , 20 Limited studies suggest transvaginal DHEA may have potential benefit in vaginal atrophy; however, further studies are required. 21

Schizophrenia

Uncontrolled studies conducted in the 1950s found an improved sense of well-being with DHEA supplementation; however, data from recent clinical trials are limited and equivocal. 3 Some evidence exists of altered DHEA/S circulating levels in patients with schizophrenia, and differences in baseline levels may account for equivocal results demonstrated in clinical studies. 22 At dosages of 150 mg/day over 12 weeks, improved negative symptoms (loss of interest, energy, and humor) were demonstrated with no effect on hallucinations or delirium. Another study used DHEA 200 mg/day for 6 weeks and found no superiority over placebo. 3

Systemic lupus erythematosus

The use of DHEA in systemic lupus erythematosus is controversial and based on the observed effects of DHEA and DHEAS on the immune system and enhanced autoantibody production by estrogen and suppression by androgens. 1 , 6

A Cochrane review of 7 studies evaluating the use of DHEA in mild to moderate systemic lupus erythematosus found little clinical effect, with only 1 study showing stabilization or improvement over placebo (8% more patients). Modest, clinically relevant increases in health-related quality of life measures were found in the review, but the long-term effect (longer than 1 year) of it supplementation is unknown. 23 , 24 The use of DHEA in more severe lupus is not supported because it exerts antiglucocorticoid effects. 1

Other uses
Asthma

Circulating DHEA/DHEAS levels have been shown to be lower among patients with asthma. 25 Nebulized DHEAS (70 mg/day) was evaluated in a study of moderate to severe asthma. No effect was demonstrated on the forced expiratory volume at 1 second or peak expiratory flow rate; however, a difference over placebo was shown using the Asthma Control Questionnaire. 26

CNS effects

DHEA supplementation may be of benefit in posttraumatic stress disorder and in improving abstinence in addiction. 3 , 27 The role of exogenous DHEA in depression remains uncertain. A correlation between low DHEA levels in elderly women and increased symptoms of depression has been suggested. Two well-designed studies found modest effects. 1

Immune effects

Correlations between circulating DHEA/DHEAS levels and urticaria and other immune-related disorders has led to proposals for DHEA supplementation. However, clinical trials are largely lacking. 28 , 29 , 30 In 1 study, no effect of DHEA supplementation was found in well-established rheumatoid arthritis. 24 Decreased disease activity was observed in a study of patients with inflammatory bowel disease. However, the study was not placebo controlled. 24 Animal studies of experimental sepsis and trauma have shown DHEA to decrease splenocyte proliferation and increase circulating NK cells and CD8+ lymphocytes; a role in managing critical illness has been suggested as a result. 31

Physical strength

Data are inconclusive on the effect of supplemental DHEA on muscle strength or physical function in elderly patients. 32

Dosage

DHEA is available as oral preparations, intraoral sprays, and transdermal creams and gels. 1

Orally administered DHEA has a low bioavailability (less than 10%), and intravenous DHEA is subject to rapid hepatic clearance. Transdermal and subcutaneous routes offer greater bioavailability. 1 Oral DHEA is converted into inactive DHEAS, which can then act as a reservoir for the body to utilize. DHEA 200 mg/day given to healthy men for 1 week resulted in a DHEA level of 1 mcg/dL and a DHEAS level of 400 mcg/dL. 1

Daily dosing of DHEA 25 mg has been suggested in postmenopausal women because this dose minimizes the androgenic adverse effects 6 ; however, only studies in which at least 50 mg/day were used demonstrated positive outcomes. 1 , 5 , 15 Dosages used in clinical studies of assisted reproduction were in the range of 50 to 75 mg/day (in divided doses). 7 , 8 , 9

In adrenal insufficiency, 50 mg/day for 3 months is considered a replacement dose, while 200 mg/day achieves supraphysiological circulating levels and would thus be considered a pharmacological dose. 5

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. DHEA supplementation has been evaluated to improve oocyte production in infertility. 7 , 8 , 9

Interactions

None well documented. 1

Adverse Reactions

Studies in adrenal insufficiency suggest DHEA is generally well tolerated. However, data from long-term studies are lacking. 4 , 6 , 23 Observed adverse effects include acne, hirsutism, and unfavorable effects on lipid metabolism (decreased HDL levels). 1 , 23 DHEA supplementation should not be used in hormone-dependent breast and prostate cancers. 1 A single case report of seizure in a woman taking DHEA to increase oocyte production exists. 7 , 8

Toxicology

Information in humans is limited. Although DHEA has been demonstrated to be carcinogenic in rodents, causing hepatic tumors, relevance in humans has been debated due to hepatic and biliary mechanisms that eliminate the suggested causative peroxisome buildup. Protective effects of DHEA on other cancers have also been demonstrated in rodents. 2 , 12

Bibliography

1. Olech E, Merrill JT. DHEA supplementation: the claims in perspective. Cleve Clin J Med . 2005;72(11):965-966, 968, 970-971 passim.
2. Webb SJ, Geoghegan TE, Prough RA, Michael Miller KK. The biological actions of dehydroepiandrosterone involves multiple receptors. Drug Metab Rev . 2006;38(1-2):89-116.
3. Maninger N, Wolkowitz OM, Reus VI, Epel ES, Mellon SH. Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Front Neuroendocrinol . 2009;30(1):65-91.
4. Grimley Evans J, Malouf R, Huppert F, van Niekerk JK. Dehydroepiandrosterone (DHEA) supplementation for cognitive function in healthy elderly people. Cochrane Database Syst Rev . 2006;(4):CD006221.
5. Genazzani AD, Lanzoni C, Genazzani AR. Might DHEA be considered a beneficial replacement therapy in the elderly? Drugs Aging . 2007;24(3):173-185.
6. Bovenberg SA, van Uum SH, Hermus AR. Dehydroepiandrosterone administration in humans: evidence based? Neth J Med . 2005;63(8):300-304.
7. Mamas L, Mamas E. Dehydroepiandrosterone supplementation in assisted reproduction: rationale and results. Curr Opin Obstet Gynecol . 2009;21(4):306-308.
8. Gleicher N, Barad DH. Dehydroepiandrosterone (DHEA) supplementation in diminished ovarian reserve (DOR). Reprod Biol Endocrinol . 2011;9:67.
9. Wiser A, Gonen O, Ghetler Y, Shavit T, Berkovitz A, Shulman A. Addition of dehydroepiandrosterone (DHEA) for poor-responder patients before and during IVF treatment improves the pregnancy rate: a randomized prospective study. Hum Reprod . 2010;25(10):2496-2500.
10. Arnold JT, Blackman MR. Does DHEA exert direct effects on androgen and estrogen receptors, and does it promote or prevent prostate cancer? Endocrinology . 2005;146(11):4565-4567.
11. Arnold JT. DHEA metabolism in prostate: For better or worse? Mol Cell Endocrinol . 2009;301(1-2):83-88.
12. Matsuzaki Y, Honda A. Dehydroepiandrosterone and its derivatives: potentially novel anti-proliferative and chemopreventive agents. Curr Pharm Des . 2006;12(26):3411-3421.
13. Sorwell KG, Urbanski HF. Dehydroepiandrosterone and age-related cognitive decline. Age (Dordr) . 2010;32(1):61-67.
14. Davis SR, Panjari M, Stanczyk FZ. Clinical review: DHEA replacement for postmenopausal women. J Clin Endocrinol Metab . 2011;96(6):1642-1653.
15. Panjari M, Davis SR. DHEA for postmenopausal women: a review of the evidence. Maturitas . 2010;66(2):172-179.
16. Tchernof A, Labrie F. Dehydroepiandrosterone, obesity and cardiovascular disease risk: a review of human studies. Eur J Endocrinol . 2004;151(1):1-14.
17. Talaei A, Amini M, Siavash M, Zare M. The effect of dehydroepiandrosterone on insulin resistance in patients with impaired glucose tolerance. Hormones (Athens) . 2010;9(4):326-331.
18. Alkatib AA, Cosma M, Elamin MB, et al. A systematic review and meta-analysis of randomized placebo-controlled trials of DHEA treatment effects on quality of life in women with adrenal insufficiency. J Clin Endocrinol Metab . 2009;94(10):3676-3681.
19. Genazzani AR, Pluchino N. DHEA therapy in postmenopausal women: the need to move forward beyond the lack of evidence. Climacteric . 2010;13(4):314-316.
20. Christiansen JJ, Bruun JM, Christiansen JS, Jørgensen JO, Gravholt CH. Long-term DHEA substitution in female adrenocortical failure, body composition, muscle function, and bone metabolism: a randomized trial. Eur J Endocrinol . 2011;165(2):293-300.
21. Panjari M, Davis SR. Vaginal DHEA to treat menopause related atrophy: a review of the evidence. Maturitas . 2011;70(1):22-25.
22. Ritsner MS. The clinical and therapeutic potentials of dehydroepiandrosterone and pregnenolone in schizophrenia. Neuroscience . 2011;191:91-100.
23. Crosbie D, Black C, McIntyre L, Royle PL, Thomas S. Dehydroepiandrosterone for systemic lupus erythematosus. Cochrane Database Syst Rev . 2007;(4):CD005114.
24. Hazeldine J, Arlt W, Lord JM. Dehydroepiandrosterone as a regulator of immune cell function. J Steroid Biochem Mol Biol . 2010;120(2-3):127-136.
25. Kasperska-Zajac A. Asthma and dehydroepiandrosterone (DHEA): facts and hypotheses. Inflammation . 2010;33(5):320-324.
26. Wenzel SE, Robinson CB, Leonard JM, Panettieri RA Jr. Nebulized dehydroepiandrosterone-3-sulfate improves asthma control in the moderate-to-severe asthma results of a 6-week, randomized, double-blind, placebo-controlled study. Allergy Asthma Proc . 2010;31(6):461-471.
27. Yadid G, Sudai E, Maayan R, Gispan I, Weizman A. The role of dehydroepiandrosterone (DHEA) in drug-seeking behavior. Neurosci Biobehav Rev . 2010;35(2):303-314.
28. Kasperska-Zajac A, Brzoza Z, Rogala B. Dehydroepiandrosterone and dehydroepiandrosterone sulphate in atopic allergy and chronic urticaria. Inflammation . 2008;31(3):141-145.
29. Kasperska-Zajac A. Does dehydroepiandrosterone influence the expression of urticaria?-a mini review. Inflammation . 2011;34(5):362-366.
30. Buford TW, Willoughby DS. Impact of DHEA(S) and cortisol on immune function in aging: a brief review. Appl Physiol Nutr Metab . 2008;33(3):429-433.
31. Oberbeck R, Kobbe P. Dehydroepiandrosterone (DHEA): a steroid with multiple effects. Is there any possible option in the treatment of critical illness? Curr Med Chem . 2010;17(11):1039-1047.
32. Baker WL, Karan S, Kenny AM. Effect of dehydroepiandrosterone on muscle strength and physical function in older adults: a systematic review. J Am Geriatr Soc . 2011;59(6):997-1002.

Copyright © 2009 Wolters Kluwer Health

Hide
(web1)